The present invention relates to novel drug treatments for neuropsychiatric disorders, for example anxiety disorders, psychotic disorders, mood disorders and somatoform disorders. These treatments relieve symptoms of disorders characterized by repetitive, stereotyped, an unwanted, intrusive, or involuntary thoughts, perceptions, or behaviors. These include posttraumatic stress disorder, obsessive-compulsive disorder, somatization disorder, hypochondriasis, and body dysmorphic disorder. Contemporary drug therapy for these conditions is limited in efficacy, with many patients continuing to have symptoms despite treatment. Antidepressants, mood stabilizers, anti-anxiety drugs, and antipsychotic drugs all have been used to treat them. Even when they provide some relief, persistent intrusive, repetitive mental phenomena may remain as a distressing symptom. Thus, when a person with posttraumatic stress disorder is treated with an antidepressant, mood may improve while xe2x80x9cflashbacksxe2x80x9d of the traumatic event continue.
Clearly, there is a need for additional medications efficacious for the treatment of these disorders, and especially for medications that suppress or eliminate the recurrent unwanted, intrusive, or involuntary thoughts, perceptions and behaviors characteristic of those disorders. Such medications might also be used to reduce such symptoms when they occur as part of another psychiatric syndrome, such as depression or schizophrenia, or when they are incidental to a neurological disorder such as Tourette""s syndrome or Huntington""s disease.
I begin by reviewing the prototypical conditions for which the novel treatment is useful:
Posttraumatic Stress Disorder (PTSD)
Description of PTSD
Posttraumatic stress disorder is an immediate or delayed response to a catastrophic event, characterized by the following features:
xe2x80x9cre-experiencing the trauma, psychic numbing or avoidance of stimuli associated with the trauma, and increased arousal. Re-experiencing phenomena include intrusive memories, flashbacks, nightmares, and psychological or physiological distress in response to trauma reminders. Intrusive memories are spontaneous, unwanted, distressing recollections of the traumatic event. Repeated nightmares contain themes of the trauma or a highly accurate and detailed re-creation of the actual event(s). Flashbacks are dissociative states in which components of the event are relived, and the person feels as if he or she is experiencing the event for a few seconds for as long as days. Reactivity to trauma-related stimuli can involve intense emotional distress or physical symptoms similar to those of a panic attack, when the patient is exposed to sights, sounds, smells or events that were present during the traumatic event. Avoidance may include thoughts, feelings, situations or activities that are reminders of the trauma. Numbing may occur through amnesia, emotional detachment, restricted affect, or loss of interest in activities. Increased arousal may include insomnia, irritability, hypervigilance, increased startle response, or impaired concentration. This disorder can have pervasive effects on an individual""s interpersonal behavior and all spheres of his or her life.xe2x80x9d (Charney D S et al.: Neurobiological mechanisms of human anxiety. In Fogel B S, Schiffer R B, Rao S M: Neuropsychiatry. Baltimore: Williams and Wilkins, 1996, pp. 257-286).
Epidemiology of PTSD
Among American veterans of the Vietnam War, the lifetime prevalence rate of PTSD was estimated as 31% in men and 27% in women; current prevalence estimates were 15% and 8.5%, respectively. In a survey of female victims of crime, the lifetime prevalence of PTSD was 13% and the current prevalence 3%. Overall, PTSD affects 2% or more of the US population (Charney et al., supra). Among people with work-related injuries, the rate of PTSD may exceed one-third, or even one-half, if people with partial PTSD syndromes are included (Asmundson G J, et al.: Posttraumatic stress disorder and work-related injury. J Anxiety Disord, 12:57-69, January-February 1998). Manifestly, PTSD is a significant public health problem.
Complications and Comorbidity
There is a strong association between PTSD and substance abuse, especially alcoholism. (Coffey S F, et al.: Screening for PTSD in a substance abuse sample: psychometric properties of a modified version of the PTSD Symptom Scale Self-Report. J Trauma Stress, 11:393-9, April 1998). In addition, chronic PTSD can increase a person""s long-term risk of a broad range of chronic diseases. Long-term follow up of men exposed to severe combat-related stress showed that PTSD significantly increased the risk of developing disorders of the circulatory, digestive, and respiratory systems as well as, infectious diseases, and neurological and psychiatric disorders other than PTSD (Boscarino J A: Diseases among men 20 years after exposure to severe stress: implications for clinical research and medical care. Psychosom. Med., 59:605-14, November-December 1997).
Various studies over the past decade have identified risk factors for the development of PTSD following an acute traumatic event. These include lower intelligence, a less developed narrative of the traumatic event, a history of prior trauma, and a rapid heart rate at the time of post-trauma medical examination. If a person develops an acute stress disorder after a major traumatic event (i.e., immediately displays symptoms resembling those of PTSD), that individual is likely to continue having symptoms, and eventually warrant, a diagnosis of PTSD. These considerations imply that a population at high risk for PTSD can be identified. If there were a non-toxic drug that significantly and specifically reduced the symptoms of PTSD, it could be used in this high-risk population to prevent the development of PTSD.
Pathophysiology of PTSD
The pathophysiology of PTSD involves disturbances in brain systems involved with reaction to stress, including the hypothalamic-pituitary-adrenal axis, and systems involving norepinephrine, serotonin, endogenous opiates, and endogenous ligands for benzodiazepine receptors. PTSD involves overactivity of the noradrenergic arousal systems, with relative underactivity of the hypothalamic-pituitary-adrenal axis (Henry JP: Psychological and physiological responses to stress: the right hemisphere and the hypothalamo-pituitary-adrenal axis, an inquiry into problems of human bonding. Acta Physiol Scand Suppl, 640:10-25, 1997). On the other hand, underactivity of endogenous opiate mechanisms may contribute to the symptoms of PTSD. (Baker D G, et al.: Cerebrospinal fluid and plasma beta-endorphin in combat veterans with post-traumatic stress disorder. Psychoneuroendocrinology, 22:517-29, October 1997)
Animal experiments suggest NMDA receptor-mediated processes are likely to be involved in the establishment of anxiety-like behavior following stressful events. The latter induce long-term potentiation (LTP) affecting connections within the amygdala, and between the amygdala and its efferents. A natural inference is that NMDA-receptor mediated processes are involved in the development of PTSD in humans (Adamec R: Transmitter systems involved in neural plasticity underlying increased anxiety and defense: implications for understanding anxiety following traumatic stress. Neuroscience and biobehavioral reviews 21(6):755-65, 1997). In a recent review, two Israeli investigators described a central role of NMDA receptors in posttraumatic stress disorder, as well as schizophrenia, alcoholism and major depression. They proposed that agents that modulate NMDA receptor function would be useful in treating all of these disorders (Heresco-Levy U, Javitt D C: The role of N-methyl-D-aspartate (NMDA) receptor-mediated neurotransmission in the pathophysiology and therapeutics of psychiatric syndromes. Eur Neuropsychopharmacol May 1998;8(2):141-52). They did not, however, propose acamprosate in the treatment of PTSD, nor the combination of NMDA receptor and GABA-A receptor actions in the treatment of these disorders.
In addition to the amygdala and its connections, PTSD involves dysfunction of the caudate nuclei. Lucey et al. (1997) in a SPECT study, showed that PTSD symptoms were negatively correlated with caudate blood flow, with the correlation stronger on the right side. (Lucey J V, et al.: Brain blood flow in anxiety disorders. OCD, panic disorder with agoraphobia, and post-traumatic stress disorder on 99mTcHMPAO single photon emission tomography (SPET). Br J Psychiatry, 171:346-50, October 1997).
The role of GABA in the pathophysiology of PTSD has not been settled. Benzodiazepines may relieve anxiety associated with PTSD. However, they usually do not do much for the specific symptoms of the disorder. In a study of trauma survivors, early administration of high-potency benzodiazepines following the trauma did not prevent the development of PTSD, even though it did reduce physiological arousal, e.g. resting heart rate (Gelpin E, et al.: Treatment of recent trauma survivors with benzodiazepines: a prospective study. J Clin Psychiatry, 57:390-4, September 1996). Moreover, the benzodiazepine antagonist flumazenil did not produce an increase in anxiety of PTSD symptoms in patients with PTSD (Randall P K, et al.: Effects of the benzodiazepine antagonist flumazenil in PTSD. Biol Psych 38(5):319-24, 1995).
Drug treatment of PTSD
Drug treatment of PTSD has had limited success. Not surprisingly in view of this, a wide range of medications have been tried. Individual patients have benefited from various drugs, but none have emerged as a standard treatment. Perhaps the most predictable benefits come from treating manifest anxiety and depression with anti-anxiety and antidepressant drugs, and from treating psychotic symptoms with antipsychotic drugs. These treatments relieve suffering and can improve function, but do not in general alter the core symptoms of intrusive thoughts and images, hyperarousal, and emotional numbing.
Classes of medications that have helped individual patients with PTSD include benzodiazepines, dopamine antagonists (neuroleptics), specific serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, antiepileptic drugs (AEDs), lithium, beta-adrenergic blockers, and clonidine (an alpha 2-adrenergic agonist), to name a few. Cyproheptadine, a serotonin receptor blocker, has shown efficacy for suppression of nightmares in patients with PTSD (Gupta S, et al.: Efficacy of cyproheptadine for nightmares associated with posttraumatic stress disorder. Compr Psychiatry, 39:160-4, May-June 1998). Recently, risperidone, an atypical neuroleptic, was shown to suppress intrusive mental phenomena in children and adolescents with PTSDxe2x80x94though it did not do so completely (Horrigan J, presentation at the American Academy of Child and Adolescent Psychiatry annual meeting, October 1998; reported in Psychiatric News, Dec. 18, 1998.)
A full-text patent search on xe2x80x9ctreatmentxe2x80x9d and xe2x80x9cposttraumatic stress disorderxe2x80x9d yielded 13 relevant patents (U.S. Pat. Nos. 5,028,612; 4,962,128; 5,484,794; 5,488,056; 5,574,028; 5,574,029; 5,574,053; 5,708,014; 5,726,193; 5,763,457; 5,776,969; 5,852,036; 5,852,037), none of which dealt with glutamate or GABA-related mechanisms. Several patents on chemicals affecting NMDA-glutamate neurotransmission include PTSD in a long list of psychiatric disorders potentially treatable with those chemicals. To date, however, no specific glutamate antagonist has been tested as a treatment for PTSD in humans. In particular, there is no literature suggesting or reporting the combination of NMDA receptor antagonists and GABA-A agonists, or the use of a drug with combined NMDA antagonist-GABA-A agonist actions, in the treatment of PTSD.
One recent publication reviews xe2x80x9cThe role of NMDA receptor-mediated neurotransmission in the pathophysiology and therapeutics of psychiatric syndromesxe2x80x9d (Heresco-Levy U, Javitt, D C, European Neuropsychopharmacology 8(1998):L 141-152). The authors note that NMDA antagonists infused into the amygdala can block the acquisition of an enhanced startle response, and infer that glutamate-dependent long-term potentiation may be critical for the development of conditioned fear and encoding of traumatic memories. However, they suggest that enhancers of NMDA receptor-mediated neurotransmission might have therapeutic effects in PTSD. They go on to state that up-regulators of NMDA neurotransmission might also reverse or prevent the cognitive deficits associated with PTSD.
Heresco-Levy and Javitt also describe the hypothesis that schizophrenia is a hypoglutamatergic state, while proposing that excessive NMDA-glutamate neurotransmission may underlie certain cases of major depression. D-cycloserine, a mixed agonist-antagonist binding to the glycine site on the NMDA receptor, is advanced as a treatment for both conditions. It is evident from this and other reviews (not enumerated here) that abnormalities of NMDA-glutamate neurotransmission are associated with psychiatric symptoms and syndromes and the various modulators of NMDA-glutamate neurotransmission are candidates for therapeutic use in mental disorders. However, available literature does not propose that NMDA antagonists would be therapeutic for PTSD, OCD, or the repetitive thoughts, perceptions, and actions that may occur as part of other neuropsychiatric disorders. The literature is totally silent on treatment with agents that combine NMDA antagonism with GABA-A agonism.
In summary, PTSD is a common disorder with significant morbidity and frequent complications, which include physical illness and substance abuse. Available drug treatment is limited in efficacy. Although a role of glutamate and NMDA receptors in the establishment of PTSD is suggested by animal models, specific NMDA receptor antagonists have not been reported as a treatment for PTSD in human patients. There exists the need for additional drugs to treat PTSD, that can provide relief of specific symptoms of the disorder, without unacceptable toxicity. An efficacious drug treatment might not only treat PTSD, but might prevent it if given soon after stress.
Obsessive-Compulsive Disorder
Description of OCD
Obsessive-compulsive disorder (OCD) is an anxiety disorder characterized by recurrent obsessions or compulsions sufficient to cause marked distress. These behaviors are time-consuming, or significantly interfere with the person""s normal functioning, social activities, or relationships. Obsessions are recurrent ideas, thoughts, images, or impulses that enter the mind and are persistent, intrusive, and unwelcome. Attempts are made to ignore or suppress the thoughts, or to neutralize them with some other thought or action. The individual recognizes them as a product of his or her own mind. Compulsions are repetitive, purposeful behaviors performed in response to an obsession, and are designed to neutralize or prevent discomfort or some dreaded event or situation. However, the activity is excessive, or not connected realistically with that which it is designed to prevent. The affected person recognizes that his or her behavior is unreasonable. (Robertson M M, Yakely J: Gilles de la Tourette syndrome and obsessive-compulsive disorder. In: Fogel B S, Schiffer R B, Rao S M: Neuropsychiatry. Baltimore: Williams and Wilkins, 1996, pp.827-870).
Epidemiology of OCD
Estimates of the lifetime prevalence of OCD in the US have ranged from 1.9% to 3.2%. Milder forms of obsessive-compulsive behavior are even more common. The lifetime risk of developing OCD within a normal life span has been estimated at 5.4% (Bland R C, Newman S C, Om H: Epidemiology of psychiatric disorders in Edmonton. Acta Psychiatr Scand 77 (Suppl): 338, 1988). The disorder usually is chronic, with only about 1/3 of patients having spontaneous remissions (Robertson and Yakely, supra).
Pathophysiology of OCD
OCD is currently thought to be due to excessive activity in neural circuits involving the orbital frontal cortex, the anterior cingulate region, the caudate nucleus and the thalamus. Recurrent activity in these circuits produces the characteristic recurrent, stereotypic obsessions and compulsions. This localization of OCD has been supported by a number of brain imaging studies with differing methodologies and overlapping results (Saxena et al.: Neuroimaging and frontal-subcortical circuitry in obsessive-compulsive disorder. Br J Psychiatry Suppl 1998;(35):26-37). Saxena and colleagues hypothesize hyperactivity of an orbital frontal-subcortical circuit, due to an imbalance of tone in direct versus indirect striato-pallidal pathways. Neuropsychological testing also suggests dysfunction of orbital frontal structures and their subcortical connections (Schmidtke K, et al.: Cognitive frontal lobe dysfunction in obsessive-compulsive disorder. Biol Psychiatry, 43:666-73, May 1, 1998; Purcell R, et al.: Cognitive deficits in obsessive-compulsive disorder on tests of frontal-striatal function. Biol Psychiatry, 43:348-57, Mar 1, 1998).
From the standpoint of neurotransmitter function, the broadest scientific consensus supports a role for serotonergic system dysfunction in OCD. (Robertson and Yakely, supra) Of greatest importance is the observation that serotonin reuptake inhibitors (SRIs) are the most consistently effective drug treatments of the disorder. In addition, studies have shown differences in serotonergic transmission between OCD patients and controls. As one example of many, patients with OCD have a lesser increase in prolactin after d-fenfluramine challenge than do normal controls. (D-fenfluramine is a SRI). Furthermore, patients with more blunting of the prolactin response tend to have worse symptoms of OCD (Monteleone, et al.: Prolactin response to d-fenfluramine in obsessive-compulsive patients, and outcome of fluvoxamine treatment. Br J Psychiatry 170:554-7, June 1997).
Dopamine may also have a role in producing the symptoms of OCD. Direct and indirect dopamine agonists, including levodopa and amphetamine, can produce stereotypical xe2x80x98ritual-likexe2x80x99 behavior in animals, and the use of stimulants in humans has been documented to produce repetitive actions resembling the compulsive behaviors of OCD (Robertson and Yakely, supra). The ability of dopamine antagonists to augment the therapeutic effects of SRIs is compatible with a hypothesis of dopaminergic hyperactivity at synapses involved in symptom production.
More recent research has suggested a role for glutamate in the production of OCD symptoms, and perhaps an ancillary role for a deficiency of GABA. Moore et al. (J. Am Acad. Child Adolesc. Psychiatry, June, 1998 37 (6):663-667) report a case of a 9-year old boy with OCD studied by PET scanning before and after successful treatment with paroxetine, a specific serotonin reuptake inhibitor (SSRI). They found major changes in glutamate resonance in the caudate region. They inferred that serotonin-glutamate interaction was involved in the pathophysiology of OCD. In a study of benzodiazepine receptors in lymphocyte membranes of patients with anxiety disorders, including OCD, patients with OCD had 25% fewer benzodiazepine binding sites than normal controls (Rocca P et al.: Peripheral-type benzodiazepine receptors in anxiety disorders. Acta Psychiatrica Scandinavica 84:6: 537-544, December 1991). This finding suggests that GABA-linked inhibition may be lacking in patients with OCD, as well as in other anxiety disorders.
Drug Treatment of OCD
SRIs (i.e., SSRIs plus clomipramine, a tricyclic antidepressant with predominant serotonin reuptake inhibition) are the mainstay of drug treatment for OCD. However, not all patients with OCD respond to SRIS, some do not tolerate them, and many have only a partial response. (Rasmussen S A, Eisen J L: Treatment strategies for chronic and refractory obsessive-compulsive disorder. J Clin Psychiatry, 58 Suppl 13:9-13, 1997). In a 1997 review, Henrietta Leonard notes that xe2x80x9cThe only agents that have shown significant improvement as augmenting agents to an SRI/SSRI in systematic trials have been clonazepam and haloperidol.xe2x80x9d (Leonard H: New developments in the treatment of obsessive-compulsive disorder. J Clin Psychiatry, 58 Suppl 14:39-45; discussion 46-7, 1997). Clonazepam is a GABA-A agonist with effects on serotonergic transmission; haloperidol a dopamine receptor blocker. Other second-line or augmenting agents, for which there is less supporting evidence, include other dopamine antagonists, lithium, clonidine (an alpha 2-adrenergic agonist), monoamine oxidase inhibitors (MAOIs), buspirone (a serotonin 1A agonist), and various other drugs that affect serotonergic transmission. Dopamine antagonists may be more useful in augmenting the response of OCD to SSRIs in patients with a personal or family history of tics (McDougle C J: Update on pharmacologic management of OCD: agents and augmentation. J Clin Psychiatry, 58 Suppl 12:11-7, 1997).
Somatoform Disorders: Somatization Disorder, Conversion Disorder, Hypochondriasis, and Body Dysmorphic Disorder
Description of Somatoform Disorders
Somatoform disorders are conditions characterized by physical symptoms without a known physiological explanation, and presumed to be caused by psychological processes. xe2x80x9cThe common feature of the Somatoform Disorders is the presence of physical symptoms that suggest a general medical condition (hence the term somatoform) and are not fully explained by a general medical condition, by the direct effects of a substance, or by another mental disorder (e.g., Panic Disorder).xe2x80x9d (American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Washington, D.C., American Psychiatric Association, 1994). Somatoform disorders are divided into a number of syndromes; complete, formal diagnostic criteria for them can be found in the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, supra). Of relevance to this application are three disorders in which repetitive, unwanted stereotyped thoughts, (in this case thoughts about somatic symptoms), are prominent:
1) Somatization Disorder is a chronic condition with onset before age 30 and duration greater than 6 months, characterized by numerous somatic complaints without demonstrable general medical causes, involving several different organ systems, and including four pain symptoms, two gastrointestinal symptoms, one sexual symptom, and one neurological symptom.
2) Conversion Disorder: unexplained sensory or motor complaints without a demonstrable general medical or neurological cause. Complaints are assessed by the clinician as being related to psychological factors.
3) Hypochondriasis is a morbid preoccupation with the fears of having, or the belief that one already has, a serious disease. These are accompanied by misinterpretation of bodily symptoms and evidence from physical examination and laboratory tests that exclude the disease with which the individual is preoccupied. The fears or beliefs cause distress and/or functional impairment, last 6 months or more, and are not relieved by medical evaluation and reassurance.
4) Body Dysmorphic Disorder: is a morbid preoccupation with an imagined defect in appearance, or grossly disproportionate concern about an actual minor physical anomaly. It is often associated with compulsive behaviors such as picking at the skin, reassurance seeking, and mirror checking (Phillips K A: Body dysmorphic disorder: diagnosis and treatment of imagined ugliness. J Clin Psychiatry, 57 Suppl 8( ):61-4).
Epidemiology of Somatoform Disorders
Estimates of prevalence vary, depending on the population studied. Obviously, the disorders are much more common in clinical samples than in the general population. However, even in the general population, the prevalence is substantial. A few recent studies illustrate this point.
1) In a community study carried out by general practitioners in two neighborhoods in Florence, Italy, the authors reported the following 1-year prevalence figures: 0.7% for somatization disorder, 0.3% for conversion disorder, 4.5% for hypochondriasis, and 0.7% for body dysmorphic disorder. (Faravelli C, et al.: Epidemiology of somatoform disorders: a community survey in Florence. Soc Psychiatry Psychiatr Epidemiol, 32(1):24-9 January 1997).
2) The prevalence of somatoform disorders in two rural primary care practices was 11.1% (Philbrick J T, et al.: The prevalence of mental disorders in rural office practice. J Gen Intern Med, 11(1):9-15 January 1996).
3) A community survey of Chinese-Americans living in Los Angeles showed a 3.6% prevalence of xe2x80x9cneurastheniaxe2x80x9d, a somatoform disorder not specified in the Diagnostic and Statistical Manual of Mental Disorders, but recognized widely as a discrete syndrome. Neurasthenia has features in common with hypchondriasis and somatization disorder. Of note, these individuals were screened to exclude anxiety disorders or depression as the cause of their somatic symptoms.
Relationship of PTSD to Somatization
Somatoform disorders, like PTSD, involve repetitive unwanted, intrusive or involuntary stereotyped thoughts, perceptions, and behaviors. In addition to this similarity, PTSD, somatization, and dissociation frequently occur together in the same patients. In a study of over 500 individuals who had been exposed to traumatic experiences, PTSD, dissociation, somatization, and affect dysregulation were highly interrelated. (van der Kolk B A, et al.: Dissociation, somatization, and affect dysregulation: the complexity of adaptation of trauma. Am J Psychiatry, 153(7 Suppl):83-93 July 1996). The authors concluded that xe2x80x9cPTSD, dissociation, somatization, and affect dysregulation represent a spectrum of adaptations to trauma. They often occur together, but traumatized individuals may suffer from various combinations of symptoms over time.xe2x80x9d Victims of torture, a most extreme stress, frequently develop a combination of somatization and PTSD (Priebe S; Esmaili S: Long-term mental sequelae of torture in Iranxe2x80x94who seeks treatment? J Nerv Ment Dis, 185(2):74-7 February 1997).
Pathophysiology of Somatoform Disorders
There has been surprisingly little research on the regional brain function in the somatoform disorders in general. However, there has been much work on regional brain function in clinical and experimental pain, using such techniques as PET scanning and functional MRI (fMRI). Similarly, much more is known about the neurochemistry of pain than about the neurochemistry of somatoform disorders. The study of pain is a valuable source of ideas related to the treatment of somatoform disorders, though obviously analgesics are not ipso facto treatments for somatoform disorders, nor would treatments for somatoform disorders necessarily be analgesics. The important link is that emotional distress related to a somatic perception is a common feature of pain and the somatoform disorders mentioned here. The physiological mechanism underlying emotional distress in the somatization disorders is likely to involve limbic system nuclei and pathways related to the emotional (as opposed to the purely sensory) aspects of pain perception. The following section summarizes some facts about pain transmission relevant to the present invention.
GABA, Glutamate, and Pain
Patients with some types of somatoform disorders experience pain. Pain transmission and modulation in the spinal cord are strongly affected by GABA and glutamate. NMDA-receptor mediated processes are involved in the development of states of hypersensitivity to pain. xe2x80x9cInformation concerning amplification systems in the spinal cord, such as the NMDA receptor, is a step toward understanding why and how a painful response is not always matched to the stimulus. Such events have parallels with other plastic events such as long-term potentiation (LTP) in the hippocampusxe2x80x9d (Dickenson A H, et al.: The pharmacology of excitatory and inhibitory amino acid-mediated events in the transmission and modulation of pain in the spinal cord. Gen Pharmacol, 28(5):633-8 May 1997). Ultimately, the balance of NMDA-mediated amplification and GABA-mediated attenuation determines the intensity of the pain signal transmitted from the spinal cord to the brain. Dickenson et al. (supra) observe that in inflammatory conditions, increased GABA activity offsets increased glutamate activity, while in neuropathic pain, it does not. This corresponds to the clinical observation that neuropathic pain may be more excruciating than pain due to tissue damage and inflammation.
Spinal cord stimulation is used clinically to alleviate intractable pain, e.g., from cancer. In animal models, the effect of spinal cord stimulation is to decrease the release of glutamate and aspartate at the dorsal horns, and to increase the release of GABA (Cui J G, et al.: Spinal cord stimulation attenuates augmented dorsal horn release of excitatory amino acids in mononeuropathy via a GABAergic mechanism. Pain, 73(1):87-95 October 1997). This supports the idea that more GABA and less glutamate (in the vicinity of NMDA receptors) is associated with analgesia. The spontaneous activity of dorsal horn neurons is suppressed by GABA and increased by glutamate, via an NMDA-receptor dependent mechanism. Augmented release of GABA partially explains the analgesic benefits of transcutaneous electrical nerve stimulation (TENS). In a cat model, the analgesic effects of electrical stimulation of peripheral nerves were partially blocked by picrotoxin, a GABA-A antagonistxe2x80x94suggesting a GABA-A mediated component (Jeong Y, et al.: Effects of iontophoretically applied naloxone, picrotoxin and strychnine on dorsal horn neuron activities treated with high frequency conditioning stimulation in cats. Yonsei Med J, 36(4):336-47 September 1995).
Based on similar studies involving the brain as well as the spinal cord, central pain, due to damage to the brain or spinal cord, has been attributed to a combination of glutamatergic and GABAergic mechanisms.
xe2x80x9cRecent evidence suggests that central pain, i.e., pain due to central nervous system damage, may be due to a deranged neurotransmission between the sensory thalamus and sensory cortical areas. Central pain can be controlled either by opposing glutamate neurotransmission or potentiating GABAergic transmission. It is speculated that a relative hypofunction of the GABAergic inhibition both at thalamic and cortical levels leads to a sectorial excitatory hypertonus in those same areas, A blend of the two should mark each patient. A pharmacological dissection approach is provided that should optimize the treatment, up to now globally poor, of central pain.xe2x80x9d (Canavero S; Bonicalzi V: The neurochemistry of central pain: evidence from clinical studies, hypothesis and therapeutic implications. Pain, 74(2-3):109-14 February 1998).
Drug Treatment of Somatoform Disorders
Among the somatoform disorders, Body Dysmorphic Disorder has the best established drug treatment, SRIs. (Phillips, supra; Phillips K A, et al.: Efficacy and safety of fluvoxamine in body dysmorphic disorder. J Clin Psychiatry, 59(4):165-71 April 1998; Perugi G, et al.: Fluvoxamine in the treatment of body dysmorphic disorder (dysmorphophobia) Int Clin Psychopharmacol, 11 (4):247-54 December 1996). This is perhaps not surprising, in view of its similarity to OCD, which also responds to SRIs in many cases. Phillips points out that augmentation with buspirone or neuroleptics may be helpful in Body Dysmorphic Disorder just as it is in OCD. However, the investigators cited above note that only about ⅔ of the patients they treated improved with SRIS.
For the other somatoform disorders, antidepressants of various kinds are most often used. They often are warranted because the patient has concurrent major depression or dysthymia, but they clearly can work in cases where the somatic symptoms are not accompanied by obvious depression. The concept of xe2x80x9cmasked depressionxe2x80x9d or xe2x80x9cdepressive equivalentxe2x80x9d has been used for decades to explain these responses (Downes-Grainger E, et al.: Clinical factors associated with short-term changes in outcome of patients with somatized mental disorder in primary care. Psychol Med, 28(3):703-11 May 1998)
When patients"" somatic complaints and concerns reach delusional proportions, they may get relief from neuroleptic drugs. These, of course, have problematic long-term side effects such as tardive dyskinesia.
Some patients may get transient relief of somatic symptoms and concerns from opiates or benzodiazepines. Unfortunately, tolerance develops. Prescription drug dependence or abuse can result.
The use of SRIs for Body Dysmorphic Disorder represents significant progress; so does the awareness that many patients who amplify symptoms will benefit from antidepressant drugs, even if they do not show manifest depression. Nonetheless, not all patients will respond to these treatments. For Somatization Disorder, Conversion Disorder, and Hypochrondriasis, drug treatment to date has been less satisfactory.
The Context of the Invention
In summary, PTSD, OCD and four somatoform disordersxe2x80x94Somatization Disorder, Conversion Disorder, Hypochondriasis, and Body Dysmorphic Disorder, are neuropsychiatric disorders characterized by intrusive, repetitive stereotyped thoughts, perceptions and behaviors that cause significant distress and disability for a substantial portion of the general population. A widely effective and tolerable drug treatment would significantly improve the treatment prospects for patients suffering from these neuropsychiatric disorders. In addition, it would offer a meaningful new treatment option in psychopharmacologyxe2x80x94distinct from antidepressants, anti-anxiety drugs, mood stabilizers (e.g., lithium, valproate), and neuroleptics. Thus, it would offer a new method of treating residual symptoms of patients partially responsive to treatment with any of these established classes of psychotropic agents.
The present invention provides a method for treating: (1) neuropsychiatric disorders such as posttraumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD) and somatoform disorders, for which it alleviates characteristic symptoms; and (2) symptoms of other neuropsychiatric disorders such as Schizophrenia, Major Depression and Bipolar Disorder, whenever their symptoms include recurrent unwanted, intrusive or involuntary stereotyped, thoughts, perceptions, or behaviors. More generally, the present invention provides a method for treating any neuropsychiatric disorder, including any anxiety disorder, psychotic disorder, mood disorder or somatoform disorder.
In one aspect, the invention provides a method for treating neuropsychiatric disorders by administering a pharmacological agent, that both (i) acts directly or indirectly as an agonist at GABA-A receptors and (ii) decreases NMDA-type glutamate neurotransmission by a direct, indirect or modulatory mechanism. Specific instances include calcium N-acetylhomotaurinate (acamprosate), magnesium N-acetylhomotaurinate, other salts of N-acetylhomotaurinate, derivatives of N-acetylhomotaurinate with similar pharmacodynamic effects on GABA and NMDA-type glutamate neurotransmission, and pro-drugs that are metabolized in the liver, blood, or brain to yield N-acetylhomotaurinate or a derivative with similar pharmacodynamic effects. In another aspect, the present invention provides methods for treating neuropsychiatric disorders by administering more than one pharmacological agent that, in combination, act to increase GABA-A neurotransmission and decrease NMDA-type glutamate neurotransmission.
The present invention also provides a method for treating neuropsychiatric disorders by combining memantine, magnesium, or a non-competitive NMDA receptor antagonist with acamprosate, or another compound or mixture thereof (specifically including those enumerated in the previous paragraph) that simultaneously decreases the postsynaptic response to glutamate at NMDA-type receptors and also directly or indirectly increases GABA-A transmission. In preferred embodiments, magnesium is used as a non-competitive NMDA receptor antagonist. Alternatively, a GABA-A agonist can be combined with a compound that has both NMDA antagonist activity and GABA-A agonist activity.
In other preferred embodiments, the present invention sets forth that magnesium can augment the effect of pharmacological agents used to treat neuropsychiatric disorders including anxiety disorders such as posttraumatic stress disorder and obsessive-compulsive disorder, somatoform disorders, mood disorders, psychotic disorders and other disorders with recurrent stereotyped, thoughts, perceptions, or behaviors that are unwanted, intrusive, or involuntary. Synergistic activity of magnesium and pharmacological agents that act to simultaneously decrease NMDA-glutamate neurotransmission and augment GABA-A neurotransmission has been demonstrated previously in treatment of movement disorders. (This is detailed in co-pending application Ser. No. 09/193,892, which is incorporated herein by reference.) Thus, in the present invention, magnesium is combined with pharmacological agents that act to simultaneously decrease NMDA-glutamate neurotransmission and augment GABA-A neurotransmission to treat neuropsychiatric disorders.
In other embodiments, any combination of agents that act as NMDA receptor antagonists together with one or more agents that facilitate GABA-A neurotransmission (by acting as GABA-A receptor agonists, by increasing GABA-A release, by inhibiting the re-uptake of GABA from the synapse, or by increasing the post-synaptic response to GABA-A receptor stimulation), with or without magnesium, are used for treatment of neuropsychiatric disorders.
A pill combining agents that act as NMDA-type glutamate receptor antagonists, GABA agonists and magnesium is proposed as a specific vehicle for the delivery of this combined therapy. In addition, other oral preparations are suggested; the mixture can be delivered in a syrup, elixir, or time-release capsule. The latter is suggested as one method for prolonging the duration of action of a dose of the mixture.
In a final embodiment, agents or combinations of agents having both the activity of NMDA antagonism and GABA-A agonism are used to prevent development of PTSD in individuals exposed to extreme stress. Alternatively compositions with combined NMDA antagonism and GABA-A agonism are used to prevent symptoms of an acute stress reaction from continuing or evolving into PTSD. It is particularly preferred that these agents are used to prevent the development of substance abuse, for example alcoholism, subsequent to extreme stress or as a complication of posttraumatic stress disorder.
xe2x80x9cEffectivexe2x80x9d: xe2x80x9cEffectivexe2x80x9d as used herein in reference to dose refers to the administration of a specific amount of a pharmacologically active agent tailored to each individual patient manifesting symptoms of neuropsychiatric disorder, sufficient to cause a reduction or improvement in any of the associated symptoms, with tolerable adverse effects. Experimentally, doses of acamprosate ranging from 333 mg to 666 mg administered three to four times daily are effective. A person skilled in the art will recognize that the optimal dose of a pharmaceutical agent administered will vary from one individual to another. Dosage in individual patients should take into account the patient""s height, weight, rate of absorption and metabolism of the medication in question, and the stage of the disorder to be treated, as well as what other pharmacological agents are administered concurrently.
xe2x80x9cNon-toxicxe2x80x9d: As used herein, xe2x80x9cnon-toxicxe2x80x9d refers to the administration of a dose of a medication in question, wherein the active components in the composition cause no adverse effects intolerable to the patient to whom it is administered, or judged by the physician to be a contraindication to continuing the medication.
xe2x80x9cAcamprosatexe2x80x9d: As used herein, xe2x80x9cacamprosatexe2x80x9d refers to calcium N-acetylhomotaurinate. These two terms may be used interchangeably. xe2x80x9cN-acetylhomotaurinatexe2x80x9d and xe2x80x9cacetylhomotaurinatexe2x80x9d are used interchangeably.
xe2x80x9cAcamprosate and related compoundsxe2x80x9d: xe2x80x9cAcamprosate and related compoundsxe2x80x9d refers to calcium acetylhomotaurinate, magnesium acetyllhomotaurinate, other salts of N-acetylhomotaurinate, and acetylhomotaurine base, and those derivatives of homotaurine or acetylhomotaurine that have similar pharmacodynamic activity with respect to GABA-A and NMDA-type glutamate neurotransmission, and pro-drugs that are metabolized in the blood, liver, or brain to yield acetylhomotaurinate or derivatives with similar pharmacodynamic activity with respect to GABA-A and NMDA-type glutamate transmission. Acamprosate decreases the intracellular response of neurons stimulated by glutamate at the NMDA receptor, and enhances GABA-A transmission, at least in part by an antagonist effect on pre-synaptic GABA-B inhibitory autoreceptors. For ease of expression, I refer to acamprosate and similar compounds with similar CNS pharmacodynamics by various terms which as used herein should be regarded as synonymous: xe2x80x9cGABA agonists and NMDA antagonistsxe2x80x9d, xe2x80x9cGABA-A agonists and NMDA-antagonistsxe2x80x9d, xe2x80x9cagents that increase GABA transmission and decrease NMDA-type glutamate transmissionxe2x80x9d, xe2x80x9cGABA agonists and glutamate antagonistsxe2x80x9d, and xe2x80x9cup regulators of GABA transmission and down-regulators of NMDA-type glutamate transmissionxe2x80x9d.
xe2x80x9cGABA-A transmissionxe2x80x9d: xe2x80x9cGABA-A transmission refers to the pharmacodynamic phenomena associated with the activation of GABA-A receptors by GABA. Enhancement of GABA-A transmission may involve increasing the release of GABA, decreasing its metabolism, decreasing the re-uptake of GABA from the synapse, increasing receptor binding, or increasing the cellular effects of receptor binding.
xe2x80x9cGABA-A receptor agonistxe2x80x9d: xe2x80x9cGABA-A receptor agonistxe2x80x9d, as used herein refers to molecules that are capable of enhancing GABA-A transmission (as defined above).
xe2x80x9cNMDA receptor antagonistxe2x80x9d: As used herein, xe2x80x9cNMDA receptor antagonistxe2x80x9d is any molecule that inhibits or diminishes the postsynaptic response of NMDA-type glutamate receptors to glutamate.
xe2x80x9cNMDA-type glutamate neurotransmissionxe2x80x9d: xe2x80x9cNMDA-type glutamate Neurotransmissionxe2x80x9d is used herein to broadly refer to anything that would decrease NMDA-glutamate transmission, whether it acts before the synapse, at the receptor binding site, within the ion channel, within the cell membrane, or inside the neuron. This includes anything that reduces release of glutamate at synapses with NMDA receptors, alters the binding of glutamate to NMDA receptors or alters the number of NMDA receptors.
xe2x80x9cNeuropsychiatric disorderxe2x80x9d: As used herein, xe2x80x9cneuropsychiatric disorderxe2x80x9d is used synonymously with xe2x80x9cmental disorderxe2x80x9d, or xe2x80x9cpsychiatric disordersxe2x80x9d the term xe2x80x9cNeuropsychiatric disorders, encompasses any anxiety disorder (for example Panic Attack, Agoraphobia, Panic Disorder Without Agoraphobia, Panic Disorder With Agaropholsia, Agoraphobia Without a History of Panic Disorder, Specific Phobia, Social Phobia, Obsssive-Compulsive Disorder, Postraumatic Stress Disorder, Acute Stress Disorder, Generalized Anxiety Disorder, Anxiety Disorder Due to a General Medical Condition, and Substance-Induced Anxiety Disorder and Anxiety Disorder Not Otherwise Specified), any psychotic disorder (for example Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, Delusional Disorder, Brief Psychotic Disorder, Shared Psychotic Disorder, Psychotic Disorder Due to a General Medical Condition, and Substance-Induced Psychotic Disorder and Psychotic Disorder Not Otherwise Specified) and any mood disorder (Major Depressive Disorder, Dysthymic Disorder, Depressive Disorder Not Otherwise Specified, Bipolar I Disorder, Bipolar II Disorder, Cyclothymic Disorder, Mood Disorder Due to a General Medical Condition, Substance-Induced Mood Disorder and Mood Disorder Not Otherwise Specified) known in the art. xe2x80x9cNeuropsychiatric Disorderxe2x80x9d is used herein to refer to any neurological disease or mental disorder in which a major symptom is the occurrence of repetitive unwanted, intrusive or involuntary stereotyped thoughts, perceptions, or behaviors. Exemplary symptoms of these disorders specifically include obsessions, ruminations about fears of disease, posttraumatic xe2x80x9cflashbacksxe2x80x9d, experiences of recurrent pain in the absence of somatic disease, compulsions, and tics. Particularly preferred mental disorders with such symptoms as characteristic features include Obsessive-Compulsive Disorder (OCD), Posttraumatic Stress Disorder (PTSD), Hypochondriasis, Pain Disorder, and Somatization Disorder. Other preferred mental disorders that may have such symptoms include, but are not limited to Schizophrenia, Major Depression, and Bipolar Disorder. Neurological Disorders characterized by such symptoms include tics, Gilles de la Tourette Syndrome (TS), and focal dystonia; other neurological disorders that may have such symptoms include Huntington""s disease.
xe2x80x9cPosttraumatic stress disorderxe2x80x9d: The term xe2x80x9cposttraumatic stress disorderxe2x80x9d or xe2x80x9cPTSDxe2x80x9d as used herein to describe an anxiety disorder characterized by an immediate or delayed response to a catastrophic event, characterized by re-experiencing the trauma, psychic numbing or avoidance of stimuli associated with the trauma, and increased arousal. Re-experiencing phenomena include intrusive memories, flashbacks, nightmares, and psychological or physiological distress in response to trauma reminders. Such responses are anxiety producing and can have significant impact, both chronic and acute, on a patient""s quality of life and physical and emotional health.
xe2x80x9cObsessive-compulsive disorderxe2x80x9d: xe2x80x9cObsessive-compulsive disorderxe2x80x9d or xe2x80x9cOCDxe2x80x9d is an anxiety disorder characterized by recurrent obsessions or compulsions sufficient to cause marked distress in the individual. They are time-consuming, or they significantly interfere with the person""s normal functioning, social activities, or relationships. Obsessions are recurrent ideas, thoughts, images, or impulses that enter the mind and are persistent, intrusive, and unwelcome. Attempts are made to ignore or suppress the thoughts, or to neutralize them with some other thought or action. The individual recognizes them as a product of his or her own mind. Compulsions are repetitive, purposeful behaviors performed in response to an obsession, and are designed to neutralize or prevent discomfort or some dreaded event or situation. A common obsession concerns thoughts of contamination; excessive handwashing is a common compulsion.
xe2x80x9cTardive dyskinesiaxe2x80x9d: As used herein xe2x80x9ctardive dyskinesiaxe2x80x9d is meant to include tardive dystonia and other movement disorders related to long-term neuroleptic use. The abbreviation TD may be used in place of the term xe2x80x9ctardive dyskinesiaxe2x80x9d.
xe2x80x9cTourette""s syndromexe2x80x9d: xe2x80x9cTourette""s syndromexe2x80x9d as used herein is synonymous with xe2x80x9cGilles de la Tourette syndromesxe2x80x9d, xe2x80x9cTourette syndromexe2x80x9d, xe2x80x9cTourette disorderxe2x80x9d, and similar expressions. The abbreviation TS may be used in place of any of these terms.
xe2x80x9cBlepharospasmxe2x80x9d: As used herein, xe2x80x9cblepharospasmxe2x80x9d includes Meige syndrome, which is a combination of blepharospasm and dystonia of the face and/or neck.
xe2x80x9cTic disorderxe2x80x9d: xe2x80x9cTic disorderxe2x80x9d as used herein, refers to an abrupt repetitive movement, gesture, or utterance that often mimics a fragment of purposeful behavior. Tics are characterized by stereotyped, repetitive, but irregularly rhythmic involuntary movements. They include both motor tics and vocal (phonic) tics. Tic disorders include, for example, simple tics, multiple tics and Gilles de la Tourette syndrome, defined as multiple tics with vocalizations.
xe2x80x9cMovement disorderxe2x80x9d: xe2x80x9cMovement disorderxe2x80x9d, as used herein, is used to refer to all forms of abnormal and involuntary movements, including vocalizations. Movement disorders include, for example, tardive dyskinesia (TD), tics, Gilles de la Tourette syndrome (TS), Parkinson""s disease, Huntington""s disease, and focal dystonias such as blepharospasm.